Alzheimer's disorder (AD) is a neurodegenerative disease characterized by progressive cognitive deterioration affecting in excess of 25 million people worldwide. In addition to the characteristic dementia seen in AD, many patients exhibit a range of non-cognitive symptoms that include depression, aggression, delusions and hallucinations. Whilst the neuropathological changes associated with AD have been well characterized in post-mortem brain tissue, little is known about either the underlying etiology of the disorder or the precise mechanisms behind disease progression. In this project we propose to look beyond the traditional genetic and neuropathological etiological approaches to AD by testing the hypothesis that epigenetic phenomena play a crucial role in the development of the disorder. Using a highly-powered sequential replication design and two complementary methylomic profiling methodologies, we aim to identify epigenetic dysfunction associated with the disorder across multiple brain regions in the largest sample of well-characterized post-mortem AD brains yet investigated. We also plan to determine whether specific epigenomic signatures are associated with AD+psychosis and AD+depression clinical subtypes using a unique collection of post-mortem brains from individuals for whom detailed clinical data has been collected prior to death. Where verified promoter DNA methylation changes are consistently observed, the expression of downstream genes will be assessed using RNA obtained from the same tissue source. In addition, other epigenetic modifications linked to transcriptional regulation will be investigated using gene- specific chromatin immunoprecipitation (ChIP) to further investigate loci nominated by the genome-wide methylomic screen. Furthermore, we will utilize laser capture microdissection of affected brain tissue to investigate whether observed epigenetic changes are a consequence of the neurodegenerative processes associated with AD (i.e. differential cell death and gliosis) or the result of epigenomic changes in the remaining neurones. The final stage of our project will be to test verified epimutations, detected in our screen of post-mortem brain tissue, in peripheral blood DNA samples obtained from the same individuals prior to their death, and subsequently in a large independent collection of blood DNA samples obtained from ongoing clinical cohort studies. Our goals of identifying a) molecular changes in the brain associated with AD and associated neuropsychiatric co-morbidities, and b) peripheral epigenetic biomarkers correlated with the changes occurring in the brain has the potential to impact greatly upon the clinical diagnosis, prognosis and future treatment of AD. Given the potential reversibility of epigenetic phenomena, and previous data highlighting ways in which drugs can affect epigenetic processing in the brain, it is hoped that our analyses will highlight novel pathways for the development of therapeutic interventions for AD and the neuropsychiatric symptoms associated with the disease. Public Health Relevance: Alzheimer's disorder is a neurodegenerative disease characterized by progressive cognitive deterioration affecting in excess of 25 million people worldwide, with the total yearly treatment and care costs estimated to be ~$250 billion. In addition to the characteristic dementia seen in Alzheimer's disorder, many patients exhibit a range of non-cognitive symptoms that include depression, aggression, delusions and hallucinations;these neuropsychiatric syndromes affect >80% of patients, impacting greatly upon the manifestation, treatment and prognosis of the disorder. Increasing our understanding about the causes of the disorder is thus of great public health importance, particularly given the aging trajectory of the population. This study aims to transform our understanding about the etiology of Alzheimer's disorder by uncovering evidence for epigenetic disruption in post-mortem brain tissue and peripheral cells obtained from affected individuals.